As a result of the extensive use of antiviral drugs, the emergence of mutant viral strains that are resistant to the currently available nucleoside therapeutics has proven to be a critical problem. Using a combination of drugs that target different viral enzymes (termed highly active anti-retroviral therapy or HAART) has helped for some viruses such as HIV, however undesirable side efects and toxicity are often prevalent and reports of multidrug resistance are increasing. Moreover, combination therapies for HBC and HCV remain limited, thus the search for new therapeutics that can overcome resistance mechanisms is urgent. Recently it was reported that Tenofovir, an FDA-approved flexible acyclic nucleotide, and Etravirine, an FDA-approved flexible heterobase analogue, can overcome resistance mutations in the HIV reverse transcriptase binding site. This flexibility allows them to retain their potency against resistant strains since they can adjust conformationally and positionaly to avoid unfavorable steric or electronic interactions and subsequently engage alternate amino acid residues not previously involved in the mechanism of action. These findings are causing a paradigm shift in how medicinal chemists view flexibility in drug design. As a result, exploitation of flexibility in the nucleobase scaffold can be viewed as a powerful tool for developing drugs that can retain their effectiveness against rapidly mutating viral targets. The specific aims for this proposal are to (i) induce flexibility to the nucleobase scaffold of known nucleoside/nucleotide antiviral drugs and (ii) test their activity against four different viral polymerases/reverse transcriptases, as well as their corresponding mutant strains. The results of this preliminary study with these highly innovative flexible nucleoside analogues will provide valuable new information on antiviral drug design targeting polymerase inhibition. In addition, new and improved methodology for nucleoside analogue synthesis will likely be an outcome. As such, the scientific impact of this work goes beyond just global health research, but will also provide valuable training for students, as the synthetic organic and drug delivery methodologies and the information obtained about polymerases will be highly applicable across a broad scope of diseases.